成体干细胞是生物体内少数处于无限增殖，未分化或低分化状态并具有多种或一种分化潜能的细胞群。干细胞的能力表现在于，通过不对称分裂产生具有相反命运的两个子代细胞，一个是通过自我更新，重新产生维持干细胞特性的新干细胞；而另一个子细胞则步入分化程序，进而形成新的组织，或替代生物体中损伤或丢失的组织和器官以维持生命活动的延续。干细胞不对称分裂机制的研究是干细胞理论研究前沿中核心的课题。
核膜蛋白在染色质组织、基因调控、信号转导等方面起着非常重要的作用。然而至今这类蛋白的生理功能仍未阐明。以果蝇为模型，动物研究所陈大华研究组发现了一个核膜蛋白Otefin (ote) 在维持果蝇生殖干细胞（GSC）自我更新过程中起关键调控作用。通过遗传学方法，研究者证明Ote是作为内源因子来调节GSC命运的因子；进一步机制研究表明，Ote蛋白通过调控BMP/Dpp信号途径，进而关闭控制干细胞分化的关键bam基因的的转录表达来实现干细胞的自我更新。通过结构与功能的关系分析，研究者发现Ote蛋白作用位点为干细胞的核内膜，并由此推测Ote蛋白可能与BMP/Dpp信号途径的核内组分相互作用完成其功能。通过生物化学方法研究者发现Ote能够与Smad4/Medea直接发生相互作用，从而结合到bam沉默子上来调节GSC的命运。该工作的意义在于：1、证明了核膜蛋白参与干细胞的命运调控，并可能推广到哺乳动物；2、为核膜蛋白如何参与TGFβ/BMP-介导的“基因沉默”提供初步的机制性解释；3、已知编码核膜蛋白的导致人类的慢性疾病，本工作可能为解析人类的核膜蛋白的编码基因缺失相关疾病的发病机制提供一定线索。
Developmental Cell Vol 14 494-506 15 April 2008
Otefin a Nuclear membrane Protein Determines the Fate of Germline Stem Cells in Drosophila via Interaction with Smad Complexes
Xiaoyong Jiang123 Laixin Xia123 Dongsheng Chen123 Yingyue Yang12 Haidong Huang12 Lele Yang1 Qiudong Zhao1 Lijun Shen1 Jun Wang1 and Dahua Chen1Developmental Cell核膜蛋白参与干细胞调控
1 State Key Laboratory of Biomembrane and Membrane Biotechnology Institute of Zoology Chinese Academy of sciences 25 Beisihuanxi Road Haidian Beijing 100080 China
2 Graduate School Chinese Academy of sciences 25 Beisihuanxi Road Haidian Beijing 100080 China
Summary
Nuclear envelope proteins play important roles in chromatin organization gene regulation and signal transduction; however the physiological role of these proteins remains elusive. We found that otefin (ote) which encodes a nuclear lamin is essential for germline stem cell (GSC) maintenance. We show that Ote as an intrinsic factor is both necessary and sufficient to regulate GSC fate. Furthermore we demonstrate that ote is required for the Dpp/BMP signaling pathway to silence bam tranion. By structure-function analysis we demonstrate that the nuclear membrane localization of Ote is essential for its role in GSC maintenance. Finally we show that Ote physically interacts with Medea/Smad4 at the bam silencer element to regulate GSC fate. Thus we demonstrate that specific nuclear membrane components mediate signal-dependent tranional effects to control stem cell behavior.
